α-Aryl-β-ketonitriles are important building blocks in the construction of complicated molecular system including natural products and biologically important molecules. They are generally prepared from condensation of α-aryl acetonitriles with the corresponding alkyl carboxylates in the presence of a base, such as sodium ethoxide (Scheme 1)(J. Am. Chem. Soc. 1951, 73, 3763; J. Med. Chem. 1991, 34, 1721). However, α-arylacetonitriles, which are usually prepared from cyanation of the corresponding benzyl halides, sometimes are not readily accessible due to the substitution pattern on the corresponding aromatic ring.

3-Unsubstituted isoxazoles may be cleaved by bases (Advances in Heterocyclic Chemistry, 1979, 25, 147; Tandem Organic Reactions, 1992, 288; Tetrahedron Lett. 1986, 27, 2027; J. Org. Chem. 1996, 61, 5435). Claisen showed that treatment of 5-phenylisoxazole with sodium ethoxide in absolute ethanol or with aqueous sodium hydroxide at room temperature yields, after acidification, ω-cyano-acetophenone (Ber. 1891, 24, 130). Isoxazole itself is cleaved to the sodium salt of cyanoacetaldehyde (Ber. 1903, 36, 3664). The isomerization of 3-unsubstituted isoxazoles to α-cyano carbonyl compounds under the influence of bases takes place readily at room temperature (Scheme 2).

Kinetic studies on the isomerization of 3-unsubstituted isoxazoles have established that the reaction is second order (first order in base and in substrate) and that the mechanism of the reaction belongs to a concerted one-stage E2 type rather than to a two-step E1cB type (Scheme 3) (Gazz. Chim. Ital. 1960, 90, 356; Chim. Ind. (Milan), 1966, 48, 491; Gazz. Chim. Ital. 1967, 97, 185). The effective isolation of the α-cyanoketone, however, depends on the stability of the latter compound, which is often unstable and readily dimerizes and/or polymerizes (Helv. Chim. Acta, 1963, 46, 543; Ger. Offen. 2,623,170; Chem. Abstr. 1978, 88, 62159).

The α-aryl-β-ketonitriles of the present invention serve as synthetic intermediates in the preparation of a series of biologically important molecules such as corticotropin releasing factor (CRF) receptor antagonists. The present invention describes a process for preparing 3-unsubstituted 4-aryl-isoxazoles and their use in preparing α-aryl-β-ketonitriles. Although methods are available for the preparation of some substituted isoxazoles, selective, high-yielding methods which produce pure crude intermediates for the preparation of 3-unsubstituted 4-arylisoxazoles are unknown in the art.
The present invention describes a convergent preparation of substituted α-aryl-β-ketonitriles (I).

The process includes reacting a substituted isoxazole with a halogenating agent to give a haloisoxazole (Scheme 4).

The literature teaches the synthesis of 4-iodo-5-methylisoxazole by iodination of 5-methylisoxazole with I2 in the presence of a oxidizing agent such as concentrated nitric acid but gives poor conversion under the reported optimized conditions. The present invention discloses an efficient synthesis of 4-iodo-5-methylisoxazole by treating commercially available 5-methylisoxazole with NIS in strong organic acidic medium, such as trifluroacetic acid, which results in an unexpected yield and purity which is critical for commercial drug preparation.
The present invention also discloses an efficient and regioselective aromatic bromination method for the effective production of the brominated aromatic compound.
A phenyl group containing an electron donating functionality in the aromatic ring, is reacted with N-bromosuccinimide followed by reacting the lithium salt of the product with a alkylborate in situ to produce a phenyl boronic after acidic hydrolysis (Scheme 5). This intermediate is coupled directly with the haloisoxale to give the isomerization precursor (Scheme 6).


Finally, a very efficient protocol for the isomerization of 4-aryl substituted isoxazoles to the corresponding α-aryl-β-ketonitriles under the influence
of a base, such as sodium methoxide is described. (Scheme 7). Due to the efficiency of the preceeding reaction, a crude cross coupling product can be used to conduct this base-promoted isomerization reaction, providing the corresponding α-aryl-β-ketonitriles directly, with exceptional purity which is beneficial for large-scale preparation of the drug substance.

Commonly-assigned U.S. provisional application No. 08/899,242, filed Jul. 23, 1997, disclosed 2,4,7,8-tetra-substituted pyrazolo[1,5-a]-1,3,5-triazines derivatives and their use in treating CRF-related abnormalities. By improving the core structure synthesis, a convergent, and therefore more efficient synthesis has been developed. This general synthetic method has been successfully used in the large-scale synthesis of this important class of corticotropin releasing factor (CRF) receptor antagnists.